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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Serie: Wiley series in drug discovery and development
- Sprache: Englisch
- Veröffentlichungsjahr: 2022
Carbon Monoxide in Drug Discovery An insightful reference for the latest physiological and therapeutic studies of carbon monoxide In Carbon Monoxide in Drug Discovery: Basics, Pharmacology, and Therapeutic Potential, a team of distinguished authors delivers foundational knowledge, the latest research, and remaining challenges regarding the physiological roles and therapeutic efficacy of carbon monoxide (CO). The editors have included a broad selection of resources from leading experts in the field that discuss the background and physiological roles of CO, a variety of delivery forms including CO prodrugs using benign carriers, CO sensing, therapeutic applications, and clinical trials. Organized by topic to allow each chapter to be read individually, the book covers a wide range of topics, from physiological and patho-physiological mechanisms at the molecular level to clinical applications for multiple disease processes. The editors of Carbon Monoxide in Drug Discovery have created a compelling argument for shifting the accepted understanding of CO from poison to bioactive molecule with enormous clinical benefits. Readers will also benefit from: * A thorough introduction to the background and physiological actions of carbon monoxide, including endogenous CO production in sickness and in health * Comprehensive explorations of CO delivery forms, including non-carrier formulations, metal-carbonyl complexes, and organic CO donors * Practical discussions of carbon monoxide sensing and scavenging, including fluorescent probes for intracellular carbon monoxide detection * In-depth examinations of the therapeutic applications of CO, including CO in solid organ transplantation Perfect for professors, graduate students, and postdocs in the fields of biology, pharmacology, immunology, medicinal chemistry, toxicology, and drug delivery, Carbon Monoxide in Drug Discovery: Basics, Pharmacology, and Therapeutic Potential is also an invaluable resource for industrial scientists in these areas.
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Carbon Monoxide in Drug Discovery
Edited by Binghe Wang and Leo E. Otterbein
Carbon Monoxide in Drug Discovery
Basics, Pharmacology, and Therapeutic Potential
Edited by
BINGHE WANG
Georgia State University,
Atlanta, GA, USA
LEO E. OTTERBEIN
Beth Israel Deaconess Medical Center,
Boston, MA, USA
This edition first published 2022
© 2022 by John Wiley & Sons, Inc.
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The right of Binghe Wang and Leo E. Otterbein to be identified as the authors of the editorial material in this work has been asserted in accordance with law.
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Library of Congress Cataloging-in-Publication Data
Names: Wang, Binghe, 1962-author. | Otterbein, Leo E., author.
Title: Carbon monoxide in drug discovery : basics, pharmacology, and therapeutic potential / edited by Binghe Wang, Georgia State University, Atlanta, GA, USA, Leo E. Otterbein, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Description: Hoboken, NJ: John Wiley & Sons, 2022. |
Series: Wiley series in drug discovery and development | Includes bibliographical references and index.
Identifiers: LCCN 2021053082 (print) | LCCN 2021053083 (ebook) | ISBN 9781119783404 (hardback) | ISBN 9781119783411 (pdf) | ISBN 9781119783428 (epub) | ISBN 9781119783435 (ebook)
Subjects: LCSH: Drugs--Research. | Carbon monoxide.
Classification: LCC RS122 .W36 2022 (print) | LCC RS122 (ebook) | DDC 615.1072--dc23/eng/20211201
LC record available at https://lccn.loc.gov/2021053082
LC ebook record available at https://lccn.loc.gov/2021053083
Cover image created with BioRender.com and courtesy of Grace E. Otterbein
Cover design by Wiley
Set in 10/12pt WarnockPro-Regular by Integra Software Services Pvt. Ltd, Pondicherry, India
Contents
Cover
Series page
Title page
Copyright
List of Contributors
Preface: Carbon Monoxide: Promises and Challenges in Its Pharmaceutical Development
Section I General Background and Physiological Actions
1 Endogenous CO Production in Sickness and in Health
2 Molecular Mechanisms of Actions for CO: An Overview
3 Pharmacokinetic Characteristics of Carbon Monoxide
4 Carbon Monoxide and Energy Metabolism
5 Role of CO in Circadian Clock
6 Carbon Monoxide and Mitochondria
7 Carbon Monoxide, Oxygen, and Pseudohypoxia
8 Nitric Oxide in Human Physiology: Production, Regulation, and Interaction with Carbon Monoxide Signaling
9 When Carbon Monoxide Meets Hydrogen Sulfide
10 Biliverdin and Bilirubin as Parallel Products of CO Formation: Not Just Bystanders
Section II Delivery Forms
11 Delivery Systems and Noncarrier Formulations
12 Metal-Based Carbon Monoxide-Releasing Molecules (CO-RMs) as Pharmacologically Active Therapeutics
13 Organic CO Donors that Rely on Photolysis for CO Release
14 Organic Carbon Monoxide Prodrugs that Release CO Under Physiological Conditions
15 Targeted Delivery of Carbon Monoxide
16 Anesthesia-Related Carbon Monoxide Exposure
17 Natural Products that Generate Carbon Monoxide: Chemistry and Nutritional Implications
Section III Carbon Monoxide Sensing and Scavenging
18 Fluorescent Probes for Intracellular Carbon Monoxide Detection
Section IV Therapeutic Applications
19 CO in Solid Organ Transplantation
20 Carbon Monoxide in Lung Injury and Disease
21 Carbon Monoxide in Acute Brain Injury and Brain Protection
22 CO as a Protective Mediator of Liver Injury: The Role of PERK in HO-1/CO-Mediated Maintenance of Cellular Homeostasis in the Liver
23 CO and Cancer
24 CO and Diabetes
25 Carbon Monoxide and Acute Kidney Injury
26 CO as an Antiplatelet Agent: An Energy Metabolism Perspective
27 CO in Gastrointestinal Physiology and Protection
28 Carbon Monoxide and Sickle Cell Disease
29 CO and Pain Management
30 Clinical Trials of Low-Dose Carbon Monoxide
Index
Plates
End User License Agreement
List of Figures
Chapter 01
Figure 1.1 Three successive oxygenation steps of heme to CO...
Chapter 02
Figure 2.1 Chemical reactivity of NO, H
2
S, and CO in biological systems...
Figure 2.2 Activation of sGC by CO. CO is synthesized by HO...
Figure 2.3 Proposed model for how skeletal muscle HO-1 activity...
Figure 2.4 Main signaling pathways modulated by CO....
Chapter 03
Figure 3.1 Schematic plots of oxygen dissociation curves of Hb and Mb (A)...
Figure 3.2 A three-compartment model for the CO/O
2
distribution...
Figure 3.3
P
CO
in arterial and venous compartments as a function...
Figure 3.4 MbCO saturation as a function of at various predefined COHb...
Figure 3.5 MbCO saturation as a function of at predefined COHb...
Figure 3.6 NbCO saturation as a function of...
Figure 3.7 COX-CO saturation as a function of...
Figure 3.8 A two-compartment model of CO.
Figure 3.9 Elimination curves of CO after short- and long-term...
Figure 3.10 The CFK model.
Figure 3.11 Comparison of experimental data and calculated data...
Figure 3.12 A multicompartment model by Bruce and Bruce....
Figure 3.13 Correlations among CO-COX saturation level, CO concentration, and intracellular...
Figure 3.14 Simulated time-dependent COHb% changes after DCM exposure....
Figure 3.15 PK description of DHMs and CO....
Figure 3.16 Structures of CORMs involved in the discussion.
Figure 3.17 Blood COHb levels after intraperitoneal administration of CORM-3 and CORM-A1....
Figure 3.18 The general structures of the prodrugs, metabolites, and the schematic illustration of CO release.
Chapter 04
Figure 4.1 CO modulation of cell metabolism: OXPHOS, glycolysis and pentose phosphate pathway.
Chapter 05
Figure 5.1 Core TTFL in the biological clock....
Figure 5.2 Biosynthesis, metabolism, and association of heme/CO with the biological clock....
Figure 5.3 Domain structures of murine (m) core circadian clock factors....
Figure 5.4 Conformation of bHLH–PAS domains of BMAL1/CLOCK....
Figure 5.5 Reactivity of the NPAS2 PASA heme sensor domain in the wild-type and its mutants.
Figure 5.6 Structure of REV-ERBα/β. (A) DBD: DNA-binding domain (Zn finger); LBD: ligand-binding domain....
Figure 5.7 Reactivity of the human REV-ERBβ heme sensor domain.
Figure 5.8 A CO-scavenging agent, hemoCD1, 1:1 supramolecular inclusion complex...
Figure 5.9 Changes in the mRNA levels of clock genes...
Figure 5.10 Mechanism of circadian clock disruption...
Chapter 06
Figure 6.1 The reduced minus oxidized optical spectrum of the mitochondrial cytochrome
c
oxidase....
Figure 6.2 Diagram of the basic redox pathway for mitochondrial biogenesis....
Chapter 07
Figure 7.1 Cellular physiology under conditions of normoxia, hypoxia, and pseudohypoxia...
Figure 7.2 Bioactivity and interconnected enzymatic modulation of the gaseous triumvirate:...
Chapter 09
Figure 9.1 Biosynthesis and transformation of H2S in mammalian cells...
Figure 9.2 Chemical structures of heme, hematin, and hemin.
Chapter 11
Figure 11.1 Oral CO-releasing system (depicted as a microscale system)...
Figure 11.2 Therapeutic gas release system was designed to exclusively...
Figure 11.3 A membrane-based approach was also used for extracorporeal...
Figure 11.4 Light was used as a trigger to release CO from electrospun materials....
Chapter 12
Scheme 12.1 Release of CO from dimanganese decacarbonyl...
Figure 12.1 Chemical structures and properties of CORM-1, CORM-2, CORM-3,...
Figure 12.2 CORM-401, a Mn-based carbonyl complex that releases CO with...
Figure 12.3 CORM-401 delivers CO and ameliorates metabolic dysfunction...
Figure 12.4 CORM-3, in the absence of dithionite, liberates CO to O
2
Hb...
Figure 12.5 Varying the CO-releasing moiety and the linker to modulate the properties...
Figure 12.6 Therapeutic effects of HYCOs
in vivo
....
Chapter 13
Figure 13.1 Structures of some metallic photoCORMs.
Figure 13.2 Structures of some boron-containing CORMs.
Figure 13.3 Structures of organic photoCORMs.
Figure 13.4 Photoreactions of the three types of organic photoCORMs.
Chapter 14
Scheme 14.1 Chemical strategies for delivering CO by (A) cheletropic and (B) decarbonylation reactions.
Scheme 14.2 DAR
inv
reactions between TPCPD and BCN to release CO.
Scheme 14.3 An enrichment-triggered strategy for delivering CO.
Figure 14.1 Fluorescence imaging studies of CO prodrug pairs (
BW-CO-19, BW-CO-20)
...
Scheme 14.4 Approaches for tuning the release rate of unimolecular CO prodrugs.
Scheme 14.5 Structural frameworks and release mechanisms of three scaffolds of unimolecular DAR-based CO prodrugs.
Scheme 14.6 Representative structures of CO prodrugs in scaffold I.
Scheme 14.7 Representative structures of CO prodrugs in scaffold III.
Scheme 14.8 Structures of
CO-107
and
CO-114.
Scheme 14.9 A prodrug system for delivering CO and metronidazole.
Scheme 14.10 A bimolecular prodrug system for delivering CO and floxuridine.
Scheme 14.11 Esterase-sensitive CO prodrugs.
Scheme 14.12 β-Elimination-triggered CO prodrugs.
Scheme 14.13 Elimination-based water-soluble CO prodrugs.
Scheme 14.14 ROS-sensitive CO prodrugs.
Scheme 14.15 Esterase-sensitive CO prodrugs.
Scheme 14.16 CO prodrugs based on decarboxylation–decarbonylation chemistry.
Figure 14.2 COHb elevation in mice upon administration of
BW-CO-306
and
BW-CO-103
....
Figure 14.3 Applications of organic CO prodrugs in disease models.
Figure 14.4 Anti-inflammatory effects of
BW-CO-103
on RAW 264.7 cells....
Figure 14.5 Protective effects of prodrug
BW-CO-48
against LPS-induced...
Figure 14.6 The effects of
BW-CO-103
on (A) MPO activity and (B)...
Figure 14.7 CO prodrugs protect against acute liver failure....
Figure 14.8 Mice were treated with inhaled CO (iCO), oral CO (HBI-002), or a CO-prodrug...
Figure 14.9 (A) Ethanol- and (B) aspirin-induced gastric lesion areas in rats pretreated...
Figure 14.10
BW-CO-306
protects against rhabdomyolysis-induced AKI....
Chapter 15
Figure 15.1 HO-catalyzed release of CO from heme.
Figure 15.2 Examples of spontaneously releasing CO donors.
Figure 15.3 Examples of pH-sensitive CO donors.
Figure 15.4 Examples of oxidation-triggered CORMs.
Figure 15.5 GSH-triggered CORM.
Figure 15.6 Enzyme-triggered CORMs.
Figure 15.7 Metal carbonyl-based photoCORMs.
Figure 15.8 Metal-free photoCORMs.
Figure 15.9 Visible light-triggered tandem deprotection and CO release from flavonol-containing micelles....
Figure 15.10 Logic gate reactivity of appended flavonols....
Figure 15.11 Enzyme-triggered photoCORMs for localized CO delivery.
Figure 15.12 Targeted synergistic OH• and CO generation in cancer cells...
Figure 15.13 CORM@IONP.
Figure 15.14 Mitochondria-targeted CO release using click-and-release reactivity.
Figure 15.15 Mitochondria-targeted CO release versus cytosolic CO release evaluated...
Figure 15.16 Evaluation of cytosolic versus extracellular CO release using visible...
Figure 15.17 Biotin-appended photoCORM used for development of Ab–photoCORM conjugates.
Figure 15.18 Components of CO nanogenerator....
Figure 15.19 (A) Multistage assembly of FeCO–TPP@MSN@HA....
Figure 15.20 Representation of synergistic anti-inflammation....
Chapter 16
Figure 16.1 The anesthesia machine. (A) A modern-day anesthesia machine is shown....
Figure 16.2 Mechanism of CO generation from inhaled anesthetic agents....
Chapter 17
Figure 17.1 Natural product-based HMOX1 inducers set in motion protein...
Figure 17.2 (A) Some autooxidation products of ascorbic acid in the presence...
Figure 17.3 CO generation from ascorbic acid in the presence of choline...
Figure 17.4 Proposed mechanisms for the oxidative degradation of quercetin....
Figure 17.5 Postulated mechanisms of decomposition of hydroperoxyl ketoacid...
Figure 17.6 The Fenton reagent may catalyze the decomposition of 1,3-dihydroxyacetone...
Figure 17.7 Proposed probable reaction pathways between DHA and hydroxyl radical...
Figure 17.8 Degradation of rutin by
A. niger
to produce CO, protocatechuic acid...
Figure 17.9 (A) CO is formed from acireductone, an intermediate in the methionine salvage...
Figure 17.10 Formation of CO from tyrosine from the action of HydG, a radical AdoMet enzyme.
Figure 17.11 Proposed mechanism for the HydG-catalyzed production of Fe-bound CO...
Figure 17.12 HypX catalyze the decarbonylation of N
10
-formyltetrahydrofolate.
Figure 17.13 AIR undergoes a complex rearrangement reaction catalyzed by thiamin-pyrimidine...
Figure 17.14 Pyruvate fermentation in
Desulfovibrio vulgaris
may lead to formation of CO...
Chapter 18
Figure 18.1 Model of bonding between CO and a metal with d-electrons.
Figure 18.2 Categories of probes for intracellular CO detection.
Figure 18.3 COP-1 reacts with CO gas or a CORM.
Figure 18.4 CC-CO as a two-photon CO probe reported by Lin and coworkers.
Figure 18.5 ACP-1 and ACP-2 reported by Tang and coworkers show differences...
Figure 18.6 A Nile red-based probe for detecting CO with direct coordination...
Figure 18.7 A cell membrane-anchored probe for detecting CO reported by Zhang and coworkers.
Figure 18.8 A benzimidazole-based fluorescent probe for CO reported by Huang and coworkers.
Figure 18.9 Systematically modified Nile red-based CO probes reported by Klán and coworkers.
Figure 18.10 Proposed mechanism based on studies by Klán and coworkers.
Figure 18.11 Comparison of the amine groups of COP-1 and commercially available lysosome stain....
Figure 18.12 Improved probe COP-3E-Py, with morpholino chelating group and esterase cleavable...
Figure 18.13 Vinyl–Ru(II) complex for CO detection via coordination and ligand displacement.
Figure 18.14 Vinyl–Ru(II) complexes for CO and viscosity detection with a BODIPY fluorophore.
Figure 18.15 General chemical signaling mechanism for CO-responsive fluorescent probes:...
Figure 18.16 First deallylation probe PCO-1 and turn-on mechanism.
Figure 18.17 Fluorescein-based deallylation probes with product excitation/emission...
Figure 18.18 Examples of ratiometric CO deallylation probes:...
Figure 18.19 Select examples of long-wavelength emission deallylation probes for CO detection.
Figure 18.20 Analyte replacement strategy employing a flavonol-derived deallylative probe.
Figure 18.21 General strategy for nitroarene reduction probes for CORM detection.
Figure 18.22 Examples of nitroarene reduction probes for CORM detection.
Figure 18.23 Fluorogenic CO probes with alternate turn-on mechanisms:...
Chapter 19
Figure 19.1 Strategies to improve the outcome of organ transplantation by CO....
Chapter 20
Figure 20.1 Hypothetical proximal targets of CO as relevant to pulmonary cells....
Figure 20.2 Low-concentration CO elicits cell type-specific protective...
Figure 20.3 Therapeutic potential of iCO in preclinical models of pulmonary disease....
Chapter 21
Figure 21.1 Potential roles of CO in the injured brain.
Figure 21.2 Postulated neuroprotective role of CO through the Nrf2 and HO-1 pathway.
Chapter 22
Figure 22.1 A PERK-centric view of CO functions....
Figure 22.2 CO-induced ATF4 maintains hepatic homeostasis via...
Figure 22.3 Exposure to CO elicits a strong antioxidant defense...
Figure 22.4 CO-induced transcription factors, ATF4 and Nrf2, crosstalk...
Figure 22.5 CO-induced TFEB nuclear translocation increases mitochondrial...
Chapter 23
Figure 23.1 The M1/M2 polarization extremes of macrophages....
Figure 23.2 The diverse range of signals that induce
HMOX1
expression....
Figure 23.3 TME cytokine regulation of HO-1 in macrophages....
Figure 23.4 HO-1 expression in the TME....
Figure 23.5 Effects of CO on the stroma....
Figure 23.6 CO modulates NF-κB signaling in CD8
+
T-cells....
Figure 23.7 The effects of CO on angiogenesis and metastasis within the TME....
Figure 23.8 HO inhibition and angiogenesis in the TME....
Chapter 24
Figure 24.1 Nonheme-dependent mechanisms involved in CO-mediated islet function....
Chapter 26
Figure 26.1 Major mechanisms underlying the antithrombotic activity...
Figure 26.2 Simultaneous inhibition of mitochondrial respiration...
Figure 26.3 CO inhibits mitochondrial respiration and glycolysis, shunting...
Chapter 27
Figure 27.1 Overview of the role of CO prodrugs in maintenance of GI mucosal defense....
Figure 27.2 An overview of the role of CO donors in the gastric ulcer healing process....
Chapter 28
Figure 28.1 Mechanisms of action of CO in SCD.
Figure 28.2 HBI-002 provides protection against vascular stasis;...
Chapter 29
Figure 29.1 The antinociceptive actions of CO and of the...
Figure 29.2 The role of HO-1 in the analgesic effects of MOR, DOR,...
Figure 29.3 The role of HO-1 in the analgesic effects of MOR, DOR,...
List of Tables
Chapter 1
Table 1.1 Association of levels of COHb, exhaled...
Chapter 2
Table 2.1 Nonheme intracellular pathways...
Chapter 3
Table 3.1 Tissue CO concentrations from animal...
Table 3.2 Parameters used for calculations based on the CFK model
Table 3.3 COHb data of oral administration of CORMs.
Chapter 6
Table 6.1 Important Hp.
Chapter 7
Table 7.1 Normal values of
p
O
2
...
Chapter 8
Table 8.1 Rate constants for association...
Chapter 10
Table 10.1 Functional activities of linear tetrapyrroles...
Table 10.2 Cell targets of bilirubin.
Chapter 17
Table 17.1 Some examples of natural product-based...
Chapter 19
Table 19.1 Organ transplants worldwide in 2018.
Chapter 28
Table 28.1 Mechanisms of action of CO in SCD.
Table 28.2 Studies with CO administered via three...
Chapter 30
Table 30.1 Clinical trials with low-dose CO.
Table 30.2 Clinical trials with CO as API.
Table 30.3 Summary results of phase 2 kidney...
Table 30.4 Serum creatinine results of phase 2 kidney...
Table 30.5 Clinical trials with low-dose CO drug...
Table 30.6 Low-dose CO drug product comparison.
Guide
Cover
Series page
Title page
Copyright
Table of Contents
List of Contributors
Preface: Carbon Monoxide: Promises and Challenges in Its Pharmaceutical Development
Begin Reading
Index
Plates
End User License Agreement
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Notes on Contributors
Joanne E. Anstee, Faculty of Life Sciences and Medicine, School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s Hospital, London SE1 1UL, UK
James N. Arnold, Faculty of Life Sciences and Medicine, School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s Hospital, London SE1 1UL, UK
Rani Ashouri, Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease and McKnight Brain Institute, University of Florida College of Medicine, 1275 Center Drive, Biomed Sci J493, Gainesville, FL 32610, USA
John Belcher, Division of Hematology, Oncology and Transplantation, Vascular Research Center, Department of Medicine, University of Minnesota, Minneapolis, MN 55408, USA
Djamal Eddine Benrahla, Mondor Institute for Biomedical Research (IMRB), Université Paris-Est Créteil, INSERM U955, F-94010 Créteil, France
Lisa M. Berreau, Department of Chemistry & Biochemistry, Utah State University, Logan, UT 84322-0300, USA
James Byrne, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Harvard Radiation Oncology Program, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02114, USA; Division of Gastroenterology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Stefan Chlopicki, Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
Rebecca P. Chow, Department of Surgery, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA
Hun Taeg Chung, Department of Biological Sciences, University of Ulsan, Ulsan 44610, Republic of Korea; Mycos Therapeutics Inc., Ulsan 44610, Republic of Korea
Mark de Caestecker, Vanderbilt University, Nashville, TN, USA
Ladie Kimberly De La Cruz, Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA
Rodrigo Alves de Souza, Beth Israel Deaconess Medical Center in Boston, MA, USA
Daniela Dias-Pedroso, UCIBIO, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Lisbon, Portugal; CEDOC, Faculdade de Ciência Médicas/NOVA Medical School, Universidade Nova de Lisboa, 1169-056 Lisbon, Portugal
Mihyang Do, Department of Biological Sciences, University of Ulsan, Ulsan 44610, Republic of Korea
Sylvain Doré, Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease and McKnight Brain Institute, University of Florida College of Medicine, 1275 Center Drive, Biomed Sci J493, Gainesville, FL 32610, USA; Departments of Neurology, Psychiatry, Pharmaceutics, and Neuroscience, University of Florida College of Medicine, Gainesville, FL, USA
Madison Fangman, Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease and McKnight Brain Institute, University of Florida College of Medicine, 1275 Center Drive, Biomed Sci J493, Gainesville, FL 32610, USA
Roberta Foresti, Mondor Institute for Biomedical Research (IMRB), Université Paris-Est Créteil, INSERM U955, F-94010 Créteil, France
Andrew Gomperts, Hillhurst Biopharmaceuticals, Inc., 2029 Verdugo Blvd, Montrose, CA 91020, USA
Edward Gomperts, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA; Hillhurst Biopharmaceuticals, Inc., Montrose, CA 91020, USA; Division of Hematology, Oncology and Transplantation, Vascular Research Center, Department of Medicine, University of Minnesota, Minneapolis, MN 55408, USA
Stephan Immenschuh, Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
Yeonsoo Joe, Department of Biological Sciences, University of Ulsan, Ulsan 44610, Republic of Korea; Mycos Therapeutics Inc., Ulsan 44610, Republic of Korea
Patrycja Kaczara, Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
Uh-Hyun Kim, National Creative Research Laboratory for Ca2+ Signaling Network, Chonbuk National University Medical School, Jeonju 54907, Republic of Korea
Hiroaki Kitagishi, Department of Molecular Chemistry, Faculty of Science and Engineering, Doshisha University, Kyotanabe, Kyoto 610-0321, Japan
Ghee Rye Lee, Beth Israel Deaconess Medical Center, Center For Life Science, 3 Blackfan Circle, 617D, Boston, MA 02215, USA
Howard Levy, Hillhurst Biopharmaceuticals, Inc., 2029 Verdugo Blvd, Montrose, CA 91020, USA
Richard J. Levy, Department of Anesthesiology, Columbia University Medical Center, 622 W. 168th Street, New York, NY 10032, USA
Yi Liao, Department of Biomedical and Chemical Engineering and Sciences, Florida Institute of Technology, Melbourne, FL, USA
Wen Lu, Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA
Katarzyna Magierowska, Department of Physiology, Jagiellonian University Medical College, Krakow, Poland
Marcin Magierowski, Department of Physiology, Jagiellonian University Medical College, Krakow, Poland
Alexandra Mazur, Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease and McKnight Brain Institute, University of Florida College of Medicine, 1275 Center Drive, Biomed Sci J493, Gainesville, FL 32610, USA
Brian W. Michel, Department of Chemistry and Biochemistry, University of Denver, Denver, CO 80210, USA
Maryam K. Mohammed, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
Shruti Mohan, Mondor Institute for Biomedical Research (IMRB), Université Paris-Est Créteil, INSERM U955, F-94010 Créteil, France
Roberto Motterlini, Mondor Institute for Biomedical Research (IMRB), Université Paris-Est Créteil, INSERM U955, F-94010 Créteil, France
Grace E. Otterbein, University of Aberdeen School of Medical Sciences, Polwarth Building, Foresterhill, Aberdeen AB25 2ZD, UK
Leo E. Otterbein, Beth Israel Deaconess Medical Center in Boston, MA, USA
Hannah Pamplin, Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease and McKnight Brain Institute, University of Florida College of Medicine, 1275 Center Drive, Biomed Sci J493, Gainesville, FL 32610, USA
Jeongmin Park, Department of Biological Sciences, University of Ulsan, Ulsan 44610, Republic of Korea
Shruti Patel, Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease and McKnight Brain Institute, University of Florida College of Medicine, 1275 Center Drive, Biomed Sci J493, Gainesville, FL 32610, USA
Claude A. Piantadosi, Department of Medicine, Duke University School of Medicine, 200 Trent Drive, Durham, NC 27710, USA
Olga Pol, Grup de Neurofarmacologia Molecular, Institut d’Investigació Biomèdica Sant Pau, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain; Grup de Neurofarmacologia Molecular, Institut de Neurociències, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
Kamil Przyborowski, Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland
Stefan W. Ryter, Joan and Sanford I. Weill Department of Medicine, and Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical Center, New York, NY 10065, USA; Proterris, Inc., Boston, MA, USA
Ikuko Sagami, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Sakyo-ku, Kyoto 606-8522, Japan
Nils Schallner, University of Freiburg, Freiburg, Germany
Morgan R. Schneider, Department of Chemistry and Biochemistry, University of Denver, Denver, CO 80210, USA
Nuno Soares, UCIBIO, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Lisbon, Portugal; CEDOC, Faculdade de Ciência Médicas/NOVA Medical School, Universidade Nova de Lisboa, 1169-056 Lisbon, Portugal
Christoph Steiger, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
Young-Joon Surh, Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08733, Republic of Korea
Chalet Tan, Departmental of Pharmaceutics and Drug Delivery, University of Mississippi School of Pharmacy, University, MS 38677, USA
Michael S. Tift, Department of Biology and Marine Biology, University of North Carolina, Wilmington, 601 S. College Road, Wilmington, NC 28403, USA
Giovanni Traverso, Division of Gastroenterology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Greg Vercellotti, Division of Hematology, Oncology and Transplantation, Vascular Research Center, Department of Medicine, University of Minnesota, Minneapolis, MN 55408, USA
Helena L.A. Vieira, UCIBIO, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Lisbon, Portugal; CEDOC, Faculdade de Ciência Médicas/NOVA Medical School, Universidade Nova de Lisboa, 1169-056 Lisbon, Portugal
Libor Vítek, 4th Department of Internal Medicine and Institute of Clinical Biochemistry and Laboratory Diagnostics, University General Hospital and 1st Faculty of Medicine, Charles University, Prague, Czech Republic
Ryan R. Walvoord, Department of Chemistry, Ursinus College, Collegeville, PA 19426, USA
Binghe Wang, Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA
Hongjun Wang, Department of Surgery, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA; Ralph Johnson Veteran Medical Center, Charleston, SC, USA
Minjia Wang, Departmental of Pharmaceutics and Drug Delivery, University of Mississippi School of Pharmacy, University, MS 38677, USA
Rui Wang, Department of Biology, York University, Toronto, Ontario M3J 1P3, Canada
Jakob Wollborn, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02114, USA
Xiaoxiao Yang, Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA
Zhengnan Yuan, Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA
Brian S. Zuckerbraun, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
Preface
Carbon Monoxide: Promises and Challenges in Its Pharmaceutical Development
Binghe Wang and Leo E. Otterbein
Carbon monoxide (CO), one of the smallest organic natural molecules, is widely known for its toxicity. Formation of CO via incomplete combustion is a major contributing factor to accidental or intentional CO poisoning, leading to severe health consequences or death. In addition, CO is a by-product of tobacco smoking, and has been associated with some of the harmful effects of smoking. However, less known and probably far more important is the recognition of the essential physiological roles of CO as a signaling molecule in mammals. Against over more than a century of negative connotation, the last few decades have proven that CO possesses a multitude of physiological roles and therapeutic functions, including regulation of the immune response, cellular proliferation, and control of cell survival. This concept is supported by the discovery that CO is produced by all cells and more so under conditions of stress. This book comprehensively summarizes key aspects of CO’s endogenous roles, therapeutic functions, and challenges that we face in its development as a therapeutic agent. We hope this preface will provide a thread for reading this book and a bird’s-eye view of the landscape for understanding this field, and more importantly lay out the challenges ahead in understanding the detailed mechanisms of action of CO and in its development as a therapeutic agent. We have divided the book into four sections that provide a framework for the reader to follow the evolution of CO from an accepted poison to a bioactive molecule that may offer enormous clinical benefits.
Section I begins with “foundational” knowledge of the CO field, including a general background and known physiological mechanisms. Endogenous production is a prerequisite for a molecule to be an endogenous signaling molecule and CO is no exception. Therefore, the book commences with a detailed discussion of CO’s endogenous production in all cells, the enzymes involved, and the detailed chemistry of the major pathway leading to endogenous CO production during the degradation of heme by the heme oxygenases (Chapter 1), a principal player in how CO is generated by all cells. Other products from heme degradation are also discussed so as to contextualize CO’s functions (Chapter 10) as an endogenous signaling molecule. Section I also includes a comprehensive examination of the molecular targets of CO (Chapter 2), providing the molecular basis for later discussion on its physiological and therapeutic functions. The physiological, therapeutic, and/or toxicological functions of any molecule are only meaningful in the context of concentrations. Therefore, the examination of the pharmacokinetic and pharmacodynamic characteristics of CO is discussed (Chapter 3). This section also includes information on CO’s role in energy metabolism (Chapter 4), regulation of the circadian clock (Chapter 5), and mitochondrial function (Chapter 6) because these three aspects impact a large number of the reported CO effects. One very important aspect of CO is its ability to signal and its relationship with other gaseous signaling molecules: nitric oxide (Chapter 8) and hydrogen sulfide (Chapter 9). Along a similar line, CO’s functions overlap with that of oxygen in very intriguing ways, which go beyond simply competing for binding with hemoproteins (Chapter 7). Therefore, there are three chapters in this section devoted to the interplay among these four gas molecules.
Section II focuses on the development of various delivery forms of CO, which are critical to studying CO’s mechanism(s) of actions, validating its pharmacological functions, and developing CO-based therapeutics. All such delivery forms focus on going beyond inhalational delivery of CO. Chapter 11 discusses noncarrier formulations, including CO in solution, CO donors encapsulated in various types of materials, and extracorporeal delivery of CO. Chapter 12 focuses on examples of metal-immobilized carbonyls, which are also commonly referred to as CO-releasing molecules (CORMs). For a period of three decades, there was a very high level of activity in this area. Chapter 12 is only able to describe a few select examples of immobilized carbonyls as CO donors. In recent years, there has been a rapid increase in the level of interest in developing metal-free CO donors for reasons of diversity and for avoiding metal-related issues. Chapter 13 discusses metal-free CO donors that rely on photolysis for CO release. A major new direction in the field of CO donors over the past 5 years has been the development of organic CO prodrugs with tunable release rates, triggered release, and the ability to deliver multiple payloads in a single prodrug. Chapter 14 comprehensively examines this area, including discussions of the unique chemistry employed and pharmacological validation studies. This chapter also has a very important section on the proper use of controls in studying CO donors, including both organic prodrugs and metal-based CORMs. Though using proper controls is normally considered routine practice in scientific research, the unique challenges of CO-independent effects observed with some metal-based CORMs indeed elevate this issue to a prominent position. In the field of CO delivery, there is always the question of whether there is the need for targeted CO delivery. Chapter 15 summarizes recent developments in this area. In terms of CO delivery, there is one area that may offer very unique opportunities for efficacy studies and toxicity assessment. Fluorinated general anesthetics such as sevoflurane, desflurane, and isoflurane are known to decompose under basic conditions, leading to the production of CO. Such basic conditions are needed in a ventilator to remove carbon dioxide. Therefore, there is the issue of anesthesia-related CO exposure, which is the focus of Chapter 16. Chapter 17 explores various aspects of natural product-based CO production, including the mechanism(s) of the chemical reactions involved and its potential implications in terms of nutritional and/or therapeutic values. These discussions also bring in a sense of effective concentrations needed for observed activities whenever possible. The last point is very important because discussions of pharmacologic activities outside of the context related to concentration and potency have very little meaning.
Section III has only one chapter, but it represents a very important aspect of the CO field. One unique challenge in studying a gaseous signaling molecule is difficulty in detection and concentration determination. Chapter 18 describes in detail available fluorescent probes for CO detection, including intracellular detection. The chapter is meticulously written with information on detection limits and signal to noise ratios for various probes. This chapter also includes discussions of reported “CO probes” that are only able to detect certain metal-based CORMs because of metal-mediated reactions, but not CO itself.
Section IV examines the pharmacologic effects and mechanistic understandings of CO in various cell culture and animal models, including organ transplantation (Chapter 19), lung injury (Chapter 20), brain injury (Chapter 21), liver injury (Chapter 22), cancer (Chapter 23), diabetes (Chapter 24), kidney injury (Chapter 25), platelet function (Chapter 26), gastrointestinal protection (Chapter 27), sickle cell disease (Chapter 28), and pain management (Chapter 29). The title for each chapter is sufficiently self-explanatory; collectively, these chapters show the breadth of clinical applications of CO. The last chapter (Chapter 30) summarizes all human clinical trials reported so far.
With its vast therapeutic potential, major challenges remain in understanding CO’s molecular mechanism(s) of action and in its pharmaceutical development. Here, we would like to highlight some of these challenges to aid future studies. First, studying the dose–response relationship of a gaseous molecule (CO) is much more challenging than that of a traditional small molecule. The volatility of CO means that the concentration of delivery may or may not be directly related to the effective concentration of CO under a given set of conditions. Second, the mode in which it is administered, the route of delivery, the resulting tissue distribution, and the elimination are standard development matters, but fortunately CO is not metabolized to an appreciable degree, making standard ADME (absorption, distribution, metabolism, and excretion) studies unique. This delivery issue becomes more complex, however, when administering CO in a form other than a gas or a saturated liquid. For instance, the release kinetics of a CO donor or prodrug is known to affect the CO concentration and duration profiles, even in simple buffer solution. In animals, the effects may appear as the same as that observed with CO gas, but with added complexity, including the need to deconvolute the effects of CO from that of the CO donor molecule or its metabolic by-product. There have been a number of reports in recent years that attributed some of the widely reported pharmacological effects of certain CORMs to CO-independent effects. The absorption and tissue distribution may differ depending on physiology or pathophysiology, e.g., lung disease where inhaled CO diffusion will be different or liver disease where metabolism of CO donor molecules and therefore the release of CO may be altered. Other considerations include the fact that some metal-based CORMs have a wide range of chemical reactivities driven by the carrier molecule. The third challenge is the unique difficulty in studying the pharmacokinetic properties of CO. Current studies use carboxyhemoglobin (COHb) as a surrogate indicator of CO concentration. This may not be sufficient. The free concentration of CO in the blood is a very important factor to consider. There is a widely held perception that free CO concentration is always low. However, this is not correct. Though Chapter 3 addresses some of these issues, more work is needed to understand what it means to use COHb as an indicator of CO concentrations. A fourth challenge is the availability of a large number of hemoproteins in a cell, which are all potential targets for CO. How to deconvolute the effects of engaging such a large number of targets that are in constant flux is an important question, but has hardly been examined. Moreover, there are likely differences in hemoprotein distributions across different species. A fifth challenge is the issue of allometric scaling. CO’s efficacy has been widely validated in various pharmacological models in different animal species such as mice and rats and large animals including pigs and dogs. However, the large number of clinical trials has yet to demonstrate efficacy in humans in a convincing fashion. In one kidney transplant study, the results seem to be very positive (Chapter 25); however, the trials were terminated prematurely without conclusive demonstration of efficacy in a statistically significant manner. The need to understand allometric scaling is a critical first step in translating success in animal models to humans.
We hope that this book will allow the readers to see the vast potential of CO and stimulate much needed research to assess its therapeutic potential. Collectively, we would like to thank all the authors for their contributions as experts in their respective fields related to CO as well as their diligence and patience in working with us. We would also like to express our sincere appreciation of Ms Andrea Mahone in the office of B. Wang for her assistance in coordinating all aspects of this book project as well as the Wiley team for their support.
May 2021
Section I. General Background and Physiological Actions
1 Endogenous CO Production in Sickness and in Health
Ladie Kimberly De La Cruz and Binghe Wang
Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, 30303, USA
Introduction
In 1949, Sjöstrand published results supporting carbon monoxide (CO) production in humans [1], ushering in the era of studying CO as a human metabolite, a biomarker for pathological events and metabolic processes [2–4], an endogenous signaling molecule [5,6], and a potential therapeutic agent [7–9]. Over the decades, a large amount of information has been gathered to allow for a deep understanding of its production and its physiological and pathological roles. Specific to this chapter, many possible endogenous sources of CO have been described, including heme degradation, lipid oxidation, degradation of various natural products, photochemical production, and microbial production. Among these, the photochemical process does not lead to de novo production because it is a process to dissociate CO from hemoglobin (Hb). Further, there are intriguing variations of CO production rates among individuals depending on gender, menstrual cycle, developmental stage (neonates and infants), physical exercise, and various pathological conditions. All such findings are consistent with the physiological and regulatory roles of CO and its potential therapeutic implications. At this time there is limited knowledge to fully analyze all the reasons for the observed variations in CO production, their physiological and pathological implications, and molecular links among different events. However, we would like to summarize these variations in one place so as to stimulate discussions and future studies of their biological implications.
CO Production Through Heme Degradation
Very impressive studies in the 1940s and 1950s identified heme degradation as the major source of CO production in cells [10–12]. Sjöstrand demonstrated the increased CO production accompanying erythrocyte destruction, laying the foundation for studying CO production under pathological conditions [3]. The relationship between hemolysis and CO production was substantiated by the work of Engstedt in 1957 [2] and Gydell in 1960 [4]. Later, Coburn measured the rate of CO production as 0.42 ± 0.07 ml/h (range: 0.35–0.57 ml/h) based on results of 10 men ranging from 18 to 70 years of age and from 125 to 170 lb in weight [13]. Such results were said to be somewhat consistent with calculated rates of production of 0.3 ml/h from heme catabolism based on the life span of erythrocytes being approximately 120 days. Endogenous CO production due to heme degradation as first suggested by Sjöstrand [10,11] and examined by Ludwig and coworkers showed that it comes from the α-methene of heme [12]. These earlier findings laid the foundation for what will be discussed next on the subject of endogenous CO production via heme degradation. The subsequent section discusses the chemistry of the enzymatic reactions and the enzymes as well as their roles and regulations.
CO is produced in a stoichiometric ratio through heme oxygenase (HO)-mediated degradation of the heme prosthetic group of hemoproteins such as Hb. The enzymatic function of HO is the removal of heme by breaking it down to produce CO and biliverdin while also recovering free iron as end products. The cytoprotective function of HO is attributed not only to the removal of the cytotoxic free heme but also to the production of its by-products: CO and biliverdin (and then bilirubin). Two isozymes of HO are known to exist. HO-1, a member of heat shock protein 32 family, is the inducible form wherein exposure to stress stimuli can increase enzymatic activity by 100-fold [14]. In contrast, HO-2 is believed to be the constitutive form [14]. While these two enzymes catalyze the same reaction, they are products of two different genes and have different roles, regulation, and post-translational modifications [15]. A third isoform has been described but was found to be a pseudogene derived from HO-2 [16]. The biological implications of HO-1 are examined in detail in various chapters in this book and are not discussed here. There is also a chapter on the production of biliverdin and bilirubin and associated implications (Chapter 10). This section solely focuses on CO production by HO-mediated heme degradation and other pathways. However, it is important to note that CO can also stimulate HO-1 expression [17–19], forming a forward-feeding loop. Though there must be at least one “braking” mechanism in such a forward-feeding loop, it is not entirely clear yet where this “brake” is and why this mechanism is only active in certain situations. The ability for CO to bind to HO already suggests inhibitory effects [20], which may serve as one of the checkpoints. Further, there is the question as to whether the limited availability of heme could also serve as a way of “check and balance.” There may be others that have not been identified.
The chemistry of the enzymatic reactions of HO to catabolize heme is very interesting and unique in many aspects. Exclusively encountered with the unique enzyme architecture of HO, the substrate heme also functions as a prosthetic group for oxygen activation [21,22]. Overall, heme degradation takes place in three successive oxygenation steps with seven electrons (Figure 1.1) that in mammalian systems can be supplied by NADPH-cytochrome P450 reductase. Upon formation of the heme–HO complex and in the presence of an electron donor, ferric heme is reduced to ferrous heme, which then binds oxygen to form a metastable ferrous oxygenated species. Acquisition of an electron followed by protonation leads to the formation of a ferric low-spin species consistent with a ferric hydroperoxide [23]. The ferric hydroperoxide intermediate may also be generated from the direct reaction between ferric heme and H2O2; however, the reaction with O2 is faster (6.9 × 106 M−1 s−1 with O2, while 1.3 × 103 M−1 s−1 with H2O2) [24,25]. This ferric hydroperoxide intermediate then acts as the activated oxygen species that leads to the self-hydroxylation of the α-meso carbon of the porphyrin ring of heme. The proposed mechanism by which the hydroxylation of the α-meso carbon occurs includes (i) a concerted hydroxylation mechanism [26], (ii) a stepwise homolytic O bond cleavage followed by addition of resulting hydroxy radical [27], and (iii) a stepwise heterolytic bond cleavage followed by addition of generated hydroxide [28]. Upon hydroxylation, an isoporphyrin π-cation intermediate [29] loses water to finally give ferric α-meso-hydroxyheme. The first few steps are common in HO and other heme-containing monooxygenases or peroxidases such as cytochrome P450. However, while HO promotes self-hydroxylation, P450-type monooxygenases go through an alternative pathway wherein the O–O bond cleaves to give a ferryl species without hydroxylation [24]. Restrictions imposed by the HO environment, specifically a distal helix directly above the heme plane where it physically shields the three other meso carbons, leads to the regiospecific hydroxylation of the α-meso carbon only [30].
Figure 1.1 Three successive oxygenation steps of heme to CO, biliverdin, and the ferrous ion by HO action.
The second step is the CO-producing phase wherein α-meso-hydroxyheme is converted to verdoheme in the presence of one equivalent of O2. While the chemistry of the first step is fairly well studied, there are contentions regarding the need for exogenous electrons in the second step [31,32]. Furthermore, unlike the first step, oxygen activation by HO may not be required; rather ferric α-meso-hydroxyheme can undergo spontaneous autooxidation wherein O2 adds to the ring carbon next to the α-meso carbon [24,31]. As a result, there are no regiospecificity restrictions in the second step [33]. The α-meso-hydroxyheme intermediate has various resonance structures involving keto–enol and radical forms. One pathway by which the second step occurs is through the reaction of the ferrous neutral radical form with O2 in the presence of an electron followed by protonation to form the ferrous α-hydroperoxy oxophlorin [21]. This intermediate then attacks one of the pyrrole rings to form a four-membered ring, which then undergoes heterolytic rearrangement to extrude CO and form ferrous verdoheme. Another possible pathway begins with the addition of oxygen to the radical form of α-meso-hydroxyheme to generate the ferrous hydroperoxyl radical intermediate followed by an intramolecular transfer of electron from the iron center to the peroxyl radical to generate a ferric peroxide intermediate [34]. The peroxide moiety then forms a complex with the iron center to form a peroxo-bridged intermediate that subsequently undergoes heterolytic cleavage to convert the iron center to a ferryl oxo species and subsequently generating an alkoxy radical. This species undergoes extrusion of CO to form ferric verdoheme that in the presence of reducing equivalents is converted to ferrous verdoheme.
In the final step of heme degradation, four reducing equivalents and one equivalent of oxygen are required to achieve ring opening and demetallation of ferrous verdoheme to produce bilirubin and free iron. While the oxygen activation mechanism is similar to that of the first step, the binding of oxygen with ferrous verdoheme is less favorable. Furthermore, this step is also susceptible to inhibition by CO, a species that is produced in the prior step. In a study using 20% CO gas, CO–verdoheme complex forms indicating that high CO concentration does not completely inhibit the first two steps of HO-1 catalysis [35]. As opposed to other heme-containing globins such as myoglobin with a large ratio of affinities between CO and O2 (41 for myoglobin), the HO enzyme has a low ratio of affinities between CO and O2 (1.2–5.6) pointing to an inherent mechanism in HO to discriminate these two gases [20]. Binding of verdoheme to oxygen produces an intermediate similar to the ferrous hydroperoxide of the first step, which then proceeds to produce ring-opened intermediates that ultimately produce HO-bound ferric biliverdin. Consumption of one more electron leads to demetallation to produce free iron and biliverdin.
While HO is primarily known for its enzymatic degradation of heme, its nonenzymatic functions have also been reported. Despite the huge amount of literature attributing the cytoprotective effects of HO to its by-products, some argue that this is unlikely based on the limited supply of HO substrates in many tissues [15]. A mutant of the HO-1 gene of human monoblastic lymphoma cell U937, which lacks the heme-degrading activity of wild-type HO-1, exhibited protection against oxidative stress through upregulation of catalase and glutathione contents [36]. The nuclear translocation of HO-1 in response to exposure to stress conditions, although associated with reduced enzymatic activity, brings about changes to the binding of transcription factors involved in oxidative stress leading to protection against H2O2-mediated injury [37]. Furthermore, HO-1 was shown to alter gene expression and promote its transcriptional regulation via a feed-forward mechanism, which is postulated to be one way in which HO-1’s basal levels are maintained under limiting substrate concentration [38]. All these also suggest that HO-1 has CO-independent activity.
In the subsequent sections, the manifestation of endogenous CO production in healthy adults, neonates, pregnant women, during exercise, and under different pathological conditions is discussed in detail. While the origin of endogenously produced CO arises primarily from heme catabolism, other sources such as induction of P450 will also be discussed.
CO Production in Healthy Adults
To understand the roles of CO in human physiology and pathology as well as its therapeutic potential, it is important to first look at CO production in somewhat quantitative terms. The first issue is to examine CO production in healthy individuals under “normal” conditions. In a landmark study, Coburn measured the rate of CO production (from COHb levels) as 0.42 ± 0.07 ml/h (range: 0.35–0.57 ml/h) and 6.1 μl/kg/h based on results of 10 men ranging from 18 to 70 years of age and from 125 to 170 lb in weight [13]. Though the dataset was not sufficiently large to conduct multivariable analysis, there did not seem to be a direct relationship between age and CO production among this group of adults. Later studies led to levels of 6.6 ± 1.9 μl/kg/h [39,40] which substantiated the work by Coburn. If one assumes the average Hb concentration, blood volume, and life span of red blood cells to be 7.5 mm (monomer), 4 l, and 120 days respectively, then each day there is about 0.25 mmol of Hb available for CO production (about 5.6 ml/day, 0.23 ml/h). In Coburn’s report, the calculated rate of CO production from red blood cell turnover was 0.3 ml/h from heme catabolism, which was said to be in general agreement with the measured 0.42 ml/h. As an approximation, they are indeed in general agreement.
For a long time, CO production was thought to be solely from heme catabolism [41
